Mechanisms of Renal Cell Repair and Regeneration after Acute Renal Failure

Abstract

In many cases, acute renal failure (ARF) is the result of proximal tubular cell injury and death and can arise in a variety of clinical situations, especially following renal ischemia and drug or toxicant exposure. Although much research has focused on the cellular events leading to ARF, less emphasis has been placed on the mechanisms of renal cell repair and regeneration, although ARF is reversed in over half of those who acquire it. Studies using in vivo and in vitro models have demonstrated the importance of proliferation, migration, and repair of physiological functions of injured renal proximal tubular cells (RPTC) in the reversal of ARF. Growth factors have been shown to produce migration and proliferation of injured RPTC, although the specific mechanisms through which growth factors promote renal regeneration in vivo are unclear. Recently, interactions between integrins and extracellular matrix proteins such as collagen IV were shown to promote the repair of physiological functions in injured RPTC. Specifically, collagen IV synthesis and deposition following cellular injury restored integrin polarity and promoted repair of mitochondrial function and active Na ϩ transport. Furthermore, exogenous collagen IV, but not collagen I, fibronectin, or laminin, promoted the repair of physiological functions without stimulating proliferation. These findings suggest the importance of establishing and/or maintaining collagen IV-integrin interactions in the stimulation of repair of physiological functions following sublethal cellular injury. Furthermore, the pathway that stimulates repair is distinct from that of proliferation and migration and may be a viable target for pharmacological intervention.Most cases of acute renal failure (ARF) result from renal ischemia, acute drug, or toxicant exposure, affecting up to 5% of all long-term hospital patients. Despite the advent of dialysis and increasing knowledge regarding the causes and effects of ARF, nearly half of those who develop the disease do not survive, a trend that has not changed for several decades (Thadhani et al., 1996;Molitoris et al., 2000). A vast majority of research in the field of ARF has focused on the determination of events and factors that cause renal proximal tubular cell (RPTC) injury and death leading to the development of ARF. Unfortunately, the development of therapeutic strategies that are efficacious in humans with ARF has proven problematic. This suggests that the development of more successful therapies requires approaching the problem from a different vantage point (Molitoris et al., 2000). The regenerative capacity of the kidney is well documented, and more than half of noncritically ill patients who acquire ARF survive (Toback et al., 1993;Abbate and Remuzzi, 1996;Liano and Pascual, 1998). The responses of surviving RPTC are thought to be crucial to the restoration of renal function following ARF. Consequently, understanding RPTC repair and regeneration mechanisms may uncover new therapeutic targets that promote renal recovery an...

Characterization of Renal Progenitors Committed Toward Tubular Lineage and Their Regenerative Potential in Renal Tubular Injury

“…The cell source for regenerating cells is poorly understood, with the strongest evidence supporting a role for less injured tubular cells, which proliferate and migrate to replace the neighboring dead cells, and eventually reline denuded tubules restoring the structural and functional integrity of the kidney [1,2]. Consistently, genetic tagging of renal epithelium in mouse models of acute kidney injury (AKI) indicated that repair of damaged nephrons is predominantly accomplished by intrinsic, surviving cells localized within the nephron epithelium [4].…”

“…Indeed, several studies demonstrated that cells showing a mixed phenotype between parietal and proximal tubular epithelium increase at the tubuloglomerular junction during kidney growth, chronic renal disorders [20][21][22][23], or during ageing [24], suggesting that renal progenitors of Bowman's capsule may be able to change to tubular cells in these conditions. However, during AKI, repair of epithelial cells mostly depends on cells directly derived from the migration and proliferation of adjacent tubular epithelial cells [1,2]. In addition, a recent study in rodents demonstrated that proliferation of regenerating tubular epithelium following acute ischemic injury is stochastically distributed among surviving tubular cells [25].…”

“…Following acute tubular injury, the kidney undergoes a regenerative response leading in most cases to recovery of renal function [1][2][3]. The cell source for regenerating cells is poorly understood, with the strongest evidence supporting a role for less injured tubular cells, which proliferate and migrate to replace the neighboring dead cells, and eventually reline denuded tubules restoring the structural and functional integrity of the kidney [1,2].…”

Renal Ischemia/Reperfusion Injury

“…PTEC require anchorage to the BM for normal function, which is mediated by integrins' binding to ECM proteins, being collagen IV its major component. It was demonstrated previously (38) that ␤1 integrins' binding to collagen IV and not to other ECM proteins elicits signal transduction events in injured PTEC that stimulate cell survival and are important for the recovery of physiologic functions. Our results revealed that ex vivo HUTS-21 was able to increase the adherence of ischemic PTEC to collagen IV, suggesting that in vivo HUTS-21 most probably increases the adhesiveness of ␤1 integrins to the basal lamina, thus contributing to prevent renal damage.…”

Bone Marrow–Derived Myofibroblasts Contribute to the Renal Interstitial Myofibroblast Population and Produce Procollagen I after Ischemia/Reperfusion in Rats

“…Regeneration and remodeling of the kidney results in recovery of renal function and morphology by tubular epithelial cell replacement (2,3). However, tubulointerstitial remodeling, as a result of an uncontrolled balance between synthesis and degradation of extracellular matrix (ECM) proteins, also can result in tubulointerstitial fibrosis (4,5), which is an important risk factor for progressive renal function loss (6).…”